1. Name Of The Medicinal Product
OxyContin® 15 mg, 30 mg, 60 mg, 120mg prolonged release tablets
2. Qualitative And Quantitative Composition
15 mg tablet contains 13.5 mg of oxycodone as 15 mg of oxycodone hydrochloride.
30 mg tablet contains 27 mg of oxycodone as 30 mg of oxycodone hydrochloride.
60 mg tablet contains 54 mg of oxycodone as 60 mg of oxycodone hydrochloride.
120 mg tablet contains 108 mg of oxycodone as 120 mg of oxycodone hydrochloride.
For a full list of excipients see section 6.1. Also contains lactose monohydrate.
3. Pharmaceutical Form
Prolonged release, round, convex tablet.
The 15 mg tablets are grey, marked OC on one side and 15 on the other.
The 30 mg tablets are brown, marked OC on one side and 30 on the other.
The 60 mg tablets are red, marked OC on one side and 60 on the other.
The 120 mg tablets are purple, marked OC on one side and 120 on the other.
4. Clinical Particulars
4.1 Therapeutic Indications
For the treatment of moderate to severe pain in patients with cancer and post-operative pain.
For the treatment of severe pain requiring the use of a strong opioid.
4.2 Posology And Method Of Administration
OxyContin tablets should not be taken with alcoholic drinks.
OxyContin tablets must be swallowed whole, and not broken, chewed or crushed.
Elderly and adults over 18 years:
OxyContin tablets should be taken at 12-hourly intervals. The dosage is dependent on the severity of the pain, and the patient's previous history of analgesic requirements.
OxyContin is not intended for use as a prn analgesic.
Increasing severity of pain will require an increased dosage of OxyContin tablets using individual tablet strengths, either alone or in combination, to achieve pain relief. The correct dosage for any individual patient is that which controls the pain and is well tolerated for a full 12 hours. Patients should be titrated to pain relief unless unmanageable adverse drug reactions prevent this. If higher doses are necessary, increases should be made, where possible, in 25% - 50% increments. The need for escape medication more than twice a day indicates that the dosage of OxyContin tablets should be increased.
The usual starting dose for opioid naïve patients or patients presenting with severe pain uncontrolled by weaker opioids is 10 mg, 12-hourly. Some patients may benefit from a starting dose of 5 mg to minimise the incidence of side effects. The dose should then be carefully titrated, as frequently as once a day if necessary, to achieve pain relief. For the majority of patients, the maximum dose is 200 mg 12-hourly. However, a few patients may require higher doses. Doses in excess of 1000 mg have been recorded.
Patients receiving oral morphine before OxyContin therapy should have their daily dose based on the following ratio: 10 mg of oral oxycodone is equivalent to 20 mg of oral morphine. It must be emphasised that this is a guide to the dose of OxyContin tablets required. Inter-patient variability requires that each patient is carefully titrated to the appropriate dose.
Controlled pharmacokinetic studies in elderly patients (aged over 65 years) have shown that, compared with younger adults, the clearance of oxycodone is only slightly reduced. No untoward adverse drug reactions were seen based on age, therefore adult doses and dosage intervals are appropriate.
Children under 18 years:
OxyContin should not be used in patients under 18 years of age.
Adults with mild to moderate renal impairment and mild hepatic impairment:
The plasma concentration in this population may be increased. Therefore dose initiation should follow a conservative approach. Patients should be started on OxyContin 5 mg 12-hourly or OxyNorm liquid 2.5 mg 6-hourly and titrated to pain relief as described above.
Use in non-malignant pain:
Opioids are not first line therapy for chronic non-malignant pain, nor are they recommended as the only treatment. Types of chronic pain which have been shown to be alleviated by strong opioids include chronic osteoarthritic pain and intervertebral disc disease. The need for continued treatment in non-malignant pain should be assessed at regular intervals.
Cessation of therapy:
When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
4.3 Contraindications
Hypersensitivity to any of the constituents, respiratory depression, head injury, paralytic ileus, acute abdomen, delayed gastric emptying, chronic obstructive airways disease, cor pulmonale, severe bronchial asthma, hypercarbia, known oxycodone sensitivity or in any situation where opioids are contra-indicated, moderate to severe hepatic impairment, severe renal impairment (creatinine clearance <10 ml/min), chronic constipation, concurrent administration of monoamine oxidase inhibitors or within 2 weeks of discontinuation of their use. Not recommended for pre-operative use or for the first 24 hours post-operatively. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy.
4.4 Special Warnings And Precautions For Use
The major risk of opioid excess is respiratory depression. As with all narcotics, a reduction in dosage may be advisable in hypothyroidism. Use with caution in patients with raised intracranial pressure, hypotension, hypovolaemia, toxic psychosis, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, alcoholism, delirium tremens, chronic renal and hepatic disease or severe pulmonary disease, and debilitated, elderly and infirm patients. OxyContin tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, OxyContin tablets should be discontinued immediately. As with all opioid preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive OxyContin tablets for 12 hours prior to the intervention. If further treatment with OxyContin tablets is indicated then the dosage should be adjusted to the new post-operative requirement.
OxyContin 60 mg, 80 mg and 120 mg tablets should not be used in patients not previously exposed to opioids. These tablet strengths may cause fatal respiratory depression when administered to opioid naïve patients.
Intake of OxyContin tablets with alcoholic drinks should be avoided because this may lead to more frequent undesirable effects such as somnolence and respiratory depression (see Section 4.5).
As with all opioid preparations, OxyContin tablets should be used with caution following abdominal surgery as opioids are known to impair intestinal motility and should not be used until the physician is assured of normal bowel function.
For appropriate patients who suffer with chronic non-malignant pain, opioids should be used as part of a comprehensive treatment programme involving other medications and treatment modalities. A crucial part of the assessment of a patient with chronic non-malignant pain is the patient's addiction and substance abuse history. There is potential for development of psychological dependence (addiction) to opioid analgesics, including oxycodone. OxyContin tablets, like all opioids, should be avoided in patients with a history of, or present alcohol and drug abuse.
If opioid treatment is considered appropriate for the patient, then the main aim of treatment is not to minimise the dose of opioid but rather to achieve a dose which provides adequate pain relief with a minimum of side effects. There must be frequent contact between physician and patient so that dosage adjustments can be made. It is strongly recommended that the physician defines treatment outcomes in accordance with pain management guidelines. The physician and patient can then agree to discontinue treatment if these objectives are not met.
OxyContin has an abuse profile similar to other strong opioids. Oxycodone may be sought and abused by people with latent or manifest addiction disorders.
In-vitro data have demonstrated that the release rate of oxycodone from the OxyContin formulation is maintained in varying concentrations of ethanol. Therefore, patients already established on an alcohol-resistant prolonged release formulation of oxycodone should not be switched to an alternative alcohol-susceptible formulation of oxycodone.
As with other opioids, infants who are born to dependent mothers may exhibit withdrawal symptoms and may have respiratory depression at birth.
OxyContin tablets must be swallowed whole, and not broken, chewed or crushed. The administration of broken, chewed or crushed OxyContin tablets leads to a rapid release and absorption of a potentially fatal dose of oxycodone (see Section 4.9). Abuse of the tablets by parenteral administration can be expected to result in other serious adverse events, such as local tissue necrosis, infection, pulmonary granulomas, increased risk of endocarditis, and valvular heart injury, which may be fatal.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
OxyContin, like other opioids, potentiates the effects of tranquillisers, anaesthetics, hypnotics, anti-depressants, sedatives, phenothiazines, neuroleptic drugs, alcohol, other opioids, muscle relaxants and antihypertensives. Monoamine oxidase inhibitors are known to interact with narcotic analgesics, producing CNS excitation or depression with hypertensive or hypotensive crisis. Concurrent administration of quinidine, an inhibitor of cytochrome P450-2D6, resulted in an increase in oxycodone Cmax by 11%, AUC by 13%, and t½ elim. by 14%. Also an increase in noroxycodone level was observed, (Cmax by 50%; AUC by 85%, and t½ elim. by 42%). The pharmacodynamic effects of oxycodone were not altered. This interaction may be observed for other potent inhibitors of cytochrome P450-2D6 enzyme. Cimetidine and inhibitors of cytochrome P450-3A such as ketoconazole, voriconazole and erythromycin may inhibit the metabolism of oxycodone.
4.6 Pregnancy And Lactation
OxyContin tablets are not recommended for use in pregnancy nor during labour. Infants born to mothers who have received opioids during pregnancy should be monitored for respiratory depression.
Oxycodone may be secreted in breast milk and may cause respiratory depression in the newborn. OxyContin tablets should, therefore, not be used in breast-feeding mothers.
4.7 Effects On Ability To Drive And Use Machines
Oxycodone may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility. Therefore patients should not drive or operate machinery if affected.
4.8 Undesirable Effects
Adverse drug reactions are typical of full opioid agonists. Tolerance and dependence may occur (see Tolerance and Dependence, below). Constipation may be prevented with an appropriate laxative. If nausea and vomiting are troublesome, oxycodone may be combined with an anti-emetic.
Common (incidence of
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Tolerance and Dependence:
The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of OxyContin tablets may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with oxycodone, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. The opioid abstinence or withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, or increased blood pressure, respiratory rate or heart rate.
4.9 Overdose
Signs of oxycodone toxicity and overdosage are pin-point pupils, respiratory depression, hypotension and hallucinations. Circulatory failure and somnolence progressing to stupor or deepening coma, skeletal muscle flaccidity, bradycardia and death may occur in more severe cases.
The effects of overdosage will be potentiated by the simultaneous ingestion of alcohol or other psychotropic drugs.
Treatment of oxycodone overdosage: Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.
In the case of massive overdosage, administer naloxone intravenously (0.4 to 2 mg for an adult and 0.01 mg/kg body weight for children), if the patient is in a coma or respiratory depression is present. Repeat the dose at 2 minute intervals if there is no response. If repeated doses are required then an infusion of 60% of the initial dose per hour is a useful starting point. A solution of 10 mg made up in 50 ml dextrose will produce 200 micrograms/ml for infusion using an IV pump (dose adjusted to the clinical response). Infusions are not a substitute for frequent review of the patient's clinical state. Intramuscular naloxone is an alternative in the event IV access is not possible. As the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Naloxone is a competitive antagonist and large doses (4 mg) may be required in seriously poisoned patients.
For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.
The patient should be observed for at least 6 hours after the last dose of naloxone.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on oxycodone. In such cases, an abrupt or complete reversal of opioid effects may precipitate pain and an acute withdrawal syndrome.
Additional/other considerations:
• Consider activated charcoal (50 g for adults, 10 -15 g for children), if a substantial amount has been ingested within 1 hour, provided the airway can be protected. It may be reasonable to assume that late administration of activated charcoal may be beneficial for prolonged release preparations; however there is no evidence to support this.
• OxyContin tablets will continue to release and add to the oxycodone load for up to 12 hours after administration and management of oxycodone overdosage should be modified accordingly. Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug, particularly when a prolonged release formulation has been taken.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Natural opium alkaloids
ATC code: NO2A AO5
Oxycodone is a full opioid agonist with no antagonist properties. It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. Oxycodone is similar to morphine in its action. The therapeutic effect is mainly analgesic, anxiolytic, antitussive and sedative.
Endocrine system
Opioids may influence the hypothalamic-pituitary-adrenal or – gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.
Other pharmacological effects
In- vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Clinical studies
The efficacy of OxyContin tablets has been demonstrated in cancer pain, post-operative pain and severe non-malignant pain such as diabetic neuropathy, postherpetic neuralgia, low back pain and osteoarthritis. In the latter indication, treatment was continued for up to 18 months and proved effective in many patients for whom NSAIDs alone provided inadequate relief. The efficacy of OxyContin tablets in neuropathic pain was confirmed by three placebo-controlled studies.
In patients with chronic non-malignant pain, maintenance of analgesia with stable dosing was demonstrated for up to three years.
5.2 Pharmacokinetic Properties
Compared with morphine, which has an absolute bioavailability of approximately 30%, oxycodone has a high absolute bioavailability of up to 87% following oral administration. Oxycodone has an elimination half-life of approximately 3 hours and is metabolised principally to noroxycodone and oxymorphone. Oxymorphone has some analgesic activity but is present in the plasma in low concentrations and is not considered to contribute to oxycodone's pharmacological effect.
The release of oxycodone from OxyContin tablets is biphasic with an initial relatively fast release providing an early onset of analgesia followed by a more controlled release which determines the 12 hour duration of action. The mean apparent elimination half-life of OxyContin is 4.5 hours which leads to steady-state being achieved in about one day.
Release of oxycodone from OxyContin tablets is independent of pH.
OxyContin tablets have an oral bioavailability comparable with conventional oral oxycodone, but the former achieve maximal plasma concentrations at about 3 hours rather than about 1 to 1.5 hours. Peak and trough concentrations of oxycodone from OxyContin tablets 10 mg administered 12-hourly are equivalent to those achieved from conventional oxycodone 5 mg administered 6-hourly.
All strengths of OxyContin tablets are bioequivalent in terms of both rate and extent of absorption. Ingestion of a standard high-fat meal does not alter the peak oxycodone concentration or the extent of oxycodone absorption from OxyContin tablets.
Elderly
The AUC in elderly subjects is 15% greater when compared with young subjects.
Gender
Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.
Patients with renal impairment
Preliminary data from a study of patients with mild to moderate renal dysfunction show peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively and AUC values for oxycodone, noroxycodone and oxymorphone approximately 60%, 60% and 40% higher than normal subjects, respectively. There was an increase in t½ of elimination for oxycodone of only 1 hour.
Patients with mild to moderate hepatic impairment
Patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively, than normal subjects. AUC values were approximately 95% and 75% higher, respectively. Oxymorphone peak plasma concentrations and AUC values were lower by 15% to 50%. The t½ elimination for oxycodone increased by 2.3 hours.
5.3 Preclinical Safety Data
Teratogenicity
Oxycodone had no effect on fertility or early embryonic development in male and female rats at doses as high as 8 mg/kg/d. Also, oxycodone did not induce any deformities in rats at doses as high as 8 mg/kg/d or in rabbits at doses as high as 125 mg/kg/d. Dose-related increases in developmental variations (increased incidences of extra (27) presacral vertebrae and extra pairs of ribs) were observed in rabbits when the data for individual fetuses were analyzed. However, when the same data were analyzed using litters as opposed to individual fetuses, there was no dose-related increase in developmental variations although the incidence of extra presacral vertebrae remained significantly higher in the 125 mg/kg/d group compared to the control group. Since this dose level was associated with severe pharmacotoxic effects in the pregnant animals, the fetal findings may have been a secondary consequence of severe maternal toxicity.
In a study of peri- and postnatal development in rats, maternal body weight and food intake parameters were reduced for doses
Carcinogenicity
Studies of oxycodone in animals to evaluate its carcinogenic potential have not been conducted owing to the length of clinical experience with the drug substance.
Mutagenicity
The results of in-vitro and in-vivo studies indicate that the genotoxic risk of oxycodone to humans is minimal or absent at the systemic oxycodone concentrations that are achieved therapeutically.
Oxycodone was not genotoxic in a bacterial mutagenicity assay or in an in-vivo micronucleus assay in the mouse. Oxycodone produced a positive response in the in-vitro mouse lymphoma assay in the presence of rat liver S9 metabolic activation at dose levels greater than 25 μg/mL. Two in-vitro chromosomal aberrations assays with human lymphocytes were conducted. In the first assay, oxycodone was negative without metabolic activation but was positive with S9 metabolic activation at the 24 hour time point but not at other time points or at 48 hour after exposure. In the second assay, oxycodone did not show any clastogenicity either with or without metabolic activation at any concentration or time point.
In vitro dissolution data generated using the standard dissolution method, show that in the presence of ethanol, at concentrations up to 40%, the prolonged release characteristics of the OxyContin formulation were maintained and no breakdown of the prolonged release mechanism was observed.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate
Povidone
Ammoniomethacrylate co-polymer
Sorbic acid
Triacetin
Stearyl alcohol
Talc
Magnesium stearate
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol
Iron oxide (E172)
In addition the tablets contain the following:
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6.2 Incompatibilities
Not applicable
6.3 Shelf Life
Three years.
6.4 Special Precautions For Storage
Do not store above 25°C.
6.5 Nature And Contents Of Container
PVC blister packs with aluminium foil backing containing 56 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Napp Pharmaceuticals Ltd
Cambridge Science Park
Milton Road
Cambridge CB4 0GW
8. Marketing Authorisation Number(S)
PL 16950/0139-0141, 0150
9. Date Of First Authorisation/Renewal Of The Authorisation
7 September 2010
10. Date Of Revision Of The Text
11. LEGAL CATEGORY
CD (Sch 2) POM
® OxyContin and the Napp Device are Registered Trade Marks.
© 2010 Napp Pharmaceuticals Ltd.
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